Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele Pisana, Rome, Italy.
Curr Vasc Pharmacol. 2013 May;11(3):338-51. doi: 10.2174/1570161111311030008.
Thiazolidinediones (TZDs) represent a class of peroxisome proliferator-activated receptor (PPAR)γ agonists widely used as insulin-sensitizers in the treatment of type 2 diabetes mellitus (T2DM). The beneficial effects of hypoglycemic drugs, including TZDs, on the hemostatic abnormalities associated to T2DM have been formerly related to improved metabolic control, rather than to direct effects. However, in recent years the pleiotropic effects of PPARγ agonists on hemostatic function have become evident. In particular, the role of platelets as a pivotal player in diabetes complications by stimulating and sustaining inflammation has been lately acknowledged. Upon activation platelets synthesize and release many bioactive substances such as thromboxane A2 (TXA2) or pro-inflammatory mediators including CD40 ligand (CD40L) that exert autocrine and paracrine activation processes in vascular inflammation leading to cardiovascular disease (CVD). Although PPARγ is a nuclear hormone receptor, anucleate platelets also highly express this receptor and treatment with synthetic PPARγ ligands dampens the release of soluble(s)CD40L and TXA2 in thrombin-activated platelets. Moreover, PPARγ through Sirtuin1 pathway has been implicated in modulating inflammatory and atherosclerotic processes in patients with T2DM. Therefore, in T2DM, where platelet activation contributes to the pathogenesis of CVD, TZDs may have an enhanced therapeutic role, despite some potentially serious adverse side effects. This review will discuss the pleiotropic effects of PPARγ treatment on the hemostatic abnormalities associated with T2DM, with particular focus on platelet activation.
噻唑烷二酮类（TZDs）是一类过氧化物酶体增殖物激活受体（PPAR）γ激动剂，广泛用于治疗 2 型糖尿病（T2DM）的胰岛素增敏剂。降血糖药物（包括 TZDs）对与 T2DM 相关的止血异常的有益作用以前与改善代谢控制有关，而不是与直接作用有关。然而，近年来，PPARγ 激动剂对止血功能的多效作用已变得明显。特别是，血小板作为糖尿病并发症中刺激和维持炎症的关键参与者的作用最近得到了认可。血小板激活后会合成并释放许多生物活性物质，如血栓烷 A2（TXA2）或促炎介质，包括 CD40 配体（CD40L），这些物质在血管炎症中发挥自分泌和旁分泌激活作用，导致心血管疾病（CVD）。尽管 PPARγ 是一种核激素受体，但无核血小板也高度表达这种受体，合成的 PPARγ 配体治疗可抑制凝血酶激活血小板中可溶性 CD40L 和 TXA2 的释放。此外，PPARγ 通过 Sirtuin1 途径参与调节 T2DM 患者的炎症和动脉粥样硬化过程。因此，在血小板激活有助于 CVD 发病机制的 T2DM 中，TZDs 可能具有增强的治疗作用，尽管存在一些潜在的严重不良反应。本文将讨论 PPARγ 治疗对与 T2DM 相关的止血异常的多效作用，特别关注血小板激活。
